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Total synthesis of (±)-crassin acetate methyl ether
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TetrahedronLetters.Vo1.31, No.17, ~~2393~2396.1990 Priited in Great Britain
TOTAL SYNTHESIS OF (+CRASSIN
ACETATE METHYL ETHER
William G. Dauben,* Ting-zhong Wang and Randall W. Stephens
Department of Chemistty, University of California, Berkeley, CA 94720
Abstract: The total synthesis of ( f )-crassin acetate methyl ether consists of two major operations, and lactone ring formation. The basic stereochemical control unit was macrocyclization S/3-benzyloxynorboman-2-one.
Since the first structure proof some 25 years ago,’ cembranoids have become one of the most widely occutring families of diterpenes in nature. Many cembranoids isolated from the gorgonians and soft corals which feature an a-methylene lactone moiety are referred to as cembranolides. One of the first cembranolides isolated in 1962 from Caribbean gorgonian pseuabplexaura
porosa
was crassin acetate l2 which has a wide range of biological
1, R=H 2,
R=CHs
activities. Since its structure was elucidated by chemical methods and its absolute configuration was established by X-ray diffraction studies,3 it has been a challenging target for synthetic organic chemists, and only very recently, a synthesis of crassin alcohol was reported4 Here we report a total synthesis of crassin acetate methyl ether 2. The synthesis
consists
of two major operations,
macrocyclization
and lactone ring formation.
The
macrocyclization relies on a McMurry coupling for the formation of the C7,s double bond while the reactivity of the a-methylene lactone moiety in 2 necessitates its introduction at the end of the synthesis. To control the stereochemistry at C!,, C& and C,, rigid benzyloxynorbomone
35 was chosen as the building block. As shown in
Scheme 1, methylation of 3, followed by allylation with LDA and ally1 bromide gave fully substituted ketone 4 as a single diastereomer in good yield.6 Alcohol 5 was formed in 70% overaLl yield by a ketalization, hydroboration,
2393
deketalization sequence. Baeyer-Villiger oxidation of ketone 5 with peracetic acid delivered regiospecifically one lactone.7 The hydroxy group was protected as uimethysilyletboxymethyl
ether,* and the lactone 6 was reduced to
Scheme 1
d.
OTBDMS
1,g. h
e
i,j. k >
7
6
1.m. n.I
o’p,
62%
63%
(3‘
,CHO \
Reagents: (a) LDA, Mel; (b) LDA, ally1 bromide; (c)l, ethylene glycol, TsOH, 2, BHs-THP, -78 “C to rt.; HaOa, OR 3. H O+; (d) CHsCOsH. Na@Q, CHCls; (e) SEMCl, (i-Pr)$Bt; (f) LAH, 0 “C; (g) t-BUM SiCl, irm*l&o le. DMF; (h) NaH, MeI, DMF, (i) Hz, 10% Pd/C, EtOAc; (i) Swem oxidation; (k) m-CPB N HPO,, CH,Cl,; (1) LAH, 0 “C to rt; (m) NaH, BnBr, (n-Bu)$II, DMF, (n) AcOH-H20-THP (3:1:1),I* 55 o2 ; (0) MesSiCN, l&crown-6, KCN, (p) LDA, (E)-2-(4-bromomethyl-3-pentenyl)-2-methyl13dioxolane; (q) (n-Bu)@P, THF, (r) LAH, -78 ‘C to rt; (s) PivCl, EtsN, TI-IP, reflux; (t) (n-Bu),NP, HMPA, 105 ‘C, (u) 5% HCl, TI-II? (v) Tic&, Zn-Cu, DMB, reflux. a diol. The primsry hydroxy group was protected as a t-butyldimethylsilyl
ether, and the hindered tertiary alcohol
2395
was
then converted
to methyl ether 7. The fully pmtected compound 7 was debenzylated and the resulting
alcohol was oxidized to a ketone by the Swem method. Again, Baeyer-Villiger oxidation of the ketone afforded the desired lactone 8 as a single isomer. The lactone was reduced with LAH and the resulting dial was protected as a dibenzyl ether. The t-butyklimethylsilyl
ether was cleaved and the resulting alcohol was oxidized to labile
aldehyde 9. Addition of the allylic anion generated from (B)-2-methyl-2-(4-methyl-5-phenylthio-3-pentenyl)-l,3dioxolane with lithium naphthalenide to aldehyde under a variety of conditions9 gave exclusively one product with an isomerized cis-Cil,tZ double bond. In order to obtain a tram coniiguration of the double bond, some kind of tunpolung synthon
of the aldehyde carbonyl had to be considered. To this end, the aldehyde was
transformed to the cyanohydrin trimethylsilyl ether which was depmtonated and alkylated with the corresponding tram allylic bromide to give cyanohydrin derivative 10. lo Exposure of 10 to TBAP in THP for 10 min (prolonged reaction time causes epimerization of the a-carbon) gave ketone 11. This labile ketone was immediately reduced with LAH to give a 1:l mixture of isomeric alcohols; each isomer was carried through the following synthesis starting with conversion to pivalates. Keto aldehyde 12 was macrocyclized with TiC1s/Zn-Cull
in mfluxing
DME to give a mixture (t:c = 4:3,65%) of two isomers 13a and 13b which were separable by chromatography on silica gel (3% ethyl acetate/ petroleum ether). This reaction demonstrated that McMurry coupling methodology could be applied to highly oxygenated substrates, widening the scope of this method. Assignment of the C;, double bond stereochemistry in 13 was made possible by the fact that 13C NMR chemical shifts of methyl groups at trisubstituted olefins differ by about 10 ppm (trans. 13-19 ppm; cis, 22-29 ppm).‘*
Scheme 2
a b. c
OB” 01% 14
16
0 f. 0
---k
0
\
40%
\ T@ 16
OAC 2
Reagents:(a) LAH, 0 ‘C; (b) t-BuMe$iCl, imidazole, DMF, 70 “C, (c) Li, NH,; (d) Ag CO Celite, benzene; (e)l. LDA, CH2=NMe.& 2, MeI. MeOH; 3, DBU, W, (f)l. (n-Bu),NF, THF$ 2. 3% &c1, (g) Ac,O, DMAP, CH2C!12.
2396
With the 14membered ring closed, the mmaining task was to construct the lactone ring (Scheme 2). Thus, trans isomer Wa was converted to diol14 in three steps. The diol was oxidixed to the desired lactone with silver carbonate on Celite13 (Fetixon reagent) in excellent yield. Introduction
of the a-methylene
group was
accomplished with Eschenmoser’s salt. l4 Desilylation of 16. followed by acetylation, gave the tide compound which was identical in all respects to the sample prepared by methylation of natural crassin acetate. Using the same methodology, cis isomer 13b has been transformed to the isomer of the titled compound and both isomers will be evaluated for their biological activities. Acknowledgement: This research was supported by Grant No. GM 27320, National Institute of General Medical Sciences, U.S. Public Health Service. References 1.
Da&en, W. G.; Thiessen, W. E.; Resnick, P. R. .I. Am. Chem. Sot. 1962,84,2015.
2.
Weinheimer, A. J.; Ciereszko, L. S.; Eufford, D. S. Annul. Rev. N. Y. Acad. Sci. 1%0,90,917.
3.
Hossain, M. B.; vsn der Helm, D. Reel. Trav. Chim. Pay-Bas 1%9,88,1413.
4.
McMurry, J. E.; Dushin, R. G. J. Am. Chem. Sot. 1989,111,8928.
5.
Meinwald, J.; Crandall, J. K. J. Am. Chem. Sot. 1%6.88,1292.
6.
For exo selectivity of alkylation on norbornyl ketones, see: Corey, E. J.; Vatakencherry, P. A. J. Am. Chem. Sot. 1%2,84,2611.
7.
Meinwald, J.; Frauenglass, E. J. Am. Gem. Sot. 1960,82,5235.
8.
Lipshultx, B. H.; Pegram, J. J. Tetrahedron Lett. 1980,21,3343.
9.
(a) Screttas, C. G.; Micha-Screttas, M. J. Org. Gem. 1979,44,713; J.Am. Chem. Sot. 1987,10!9,4710.
10.
(a) Evans, D. A.; Truesdale, L. K. Tetrahedron Lett. 1973, 4929; (b) Hertenstein, U.; Hunig, S.; Oller, M. Synthesis 1976,416.
11.
McMurry, J. E.; Kees, K. L. J. Org. Chem. 1977,42,2655.
12.
(a) Martin, G. E.; Matson, J. A.; Turley, J. C.; Weinheimer, A. J. J. Am. Chem. Sot. 19’79, 101, 1888; (b) Kashman, Y.; Carmely, S.; Groweiss, A. J. Org. Chem. N&46,3592.
13.
Fetizon, M.; Golfier, M.; Louis, J-M. Tetrahedron 1975,31,171.
14.
Roberts, J. L.; Borromeo, P. S.; Poulter, C. D. Tetrahedron Lett. W77,1621.
(Received in USA 16 February 1990)
(b) Cohen, T.; Guo, B.; Doubleday, W.
TetrahedronLetters.Vo1.31, No.17, ~~2393~2396.1990 Priited in Great Britain
TOTAL SYNTHESIS OF (+CRASSIN
ACETATE METHYL ETHER
William G. Dauben,* Ting-zhong Wang and Randall W. Stephens
Department of Chemistty, University of California, Berkeley, CA 94720
Abstract: The total synthesis of ( f )-crassin acetate methyl ether consists of two major operations, and lactone ring formation. The basic stereochemical control unit was macrocyclization S/3-benzyloxynorboman-2-one.
Since the first structure proof some 25 years ago,’ cembranoids have become one of the most widely occutring families of diterpenes in nature. Many cembranoids isolated from the gorgonians and soft corals which feature an a-methylene lactone moiety are referred to as cembranolides. One of the first cembranolides isolated in 1962 from Caribbean gorgonian pseuabplexaura
porosa
was crassin acetate l2 which has a wide range of biological
1, R=H 2,
R=CHs
activities. Since its structure was elucidated by chemical methods and its absolute configuration was established by X-ray diffraction studies,3 it has been a challenging target for synthetic organic chemists, and only very recently, a synthesis of crassin alcohol was reported4 Here we report a total synthesis of crassin acetate methyl ether 2. The synthesis
consists
of two major operations,
macrocyclization
and lactone ring formation.
The
macrocyclization relies on a McMurry coupling for the formation of the C7,s double bond while the reactivity of the a-methylene lactone moiety in 2 necessitates its introduction at the end of the synthesis. To control the stereochemistry at C!,, C& and C,, rigid benzyloxynorbomone
35 was chosen as the building block. As shown in
Scheme 1, methylation of 3, followed by allylation with LDA and ally1 bromide gave fully substituted ketone 4 as a single diastereomer in good yield.6 Alcohol 5 was formed in 70% overaLl yield by a ketalization, hydroboration,
2393
deketalization sequence. Baeyer-Villiger oxidation of ketone 5 with peracetic acid delivered regiospecifically one lactone.7 The hydroxy group was protected as uimethysilyletboxymethyl
ether,* and the lactone 6 was reduced to
Scheme 1
d.
OTBDMS
1,g. h
e
i,j. k >
7
6
1.m. n.I
o’p,
62%
63%
(3‘
,CHO \
Reagents: (a) LDA, Mel; (b) LDA, ally1 bromide; (c)l, ethylene glycol, TsOH, 2, BHs-THP, -78 “C to rt.; HaOa, OR 3. H O+; (d) CHsCOsH. Na@Q, CHCls; (e) SEMCl, (i-Pr)$Bt; (f) LAH, 0 “C; (g) t-BUM SiCl, irm*l&o le. DMF; (h) NaH, MeI, DMF, (i) Hz, 10% Pd/C, EtOAc; (i) Swem oxidation; (k) m-CPB N HPO,, CH,Cl,; (1) LAH, 0 “C to rt; (m) NaH, BnBr, (n-Bu)$II, DMF, (n) AcOH-H20-THP (3:1:1),I* 55 o2 ; (0) MesSiCN, l&crown-6, KCN, (p) LDA, (E)-2-(4-bromomethyl-3-pentenyl)-2-methyl13dioxolane; (q) (n-Bu)@P, THF, (r) LAH, -78 ‘C to rt; (s) PivCl, EtsN, TI-IP, reflux; (t) (n-Bu),NP, HMPA, 105 ‘C, (u) 5% HCl, TI-II? (v) Tic&, Zn-Cu, DMB, reflux. a diol. The primsry hydroxy group was protected as a t-butyldimethylsilyl
ether, and the hindered tertiary alcohol
2395
was
then converted
to methyl ether 7. The fully pmtected compound 7 was debenzylated and the resulting
alcohol was oxidized to a ketone by the Swem method. Again, Baeyer-Villiger oxidation of the ketone afforded the desired lactone 8 as a single isomer. The lactone was reduced with LAH and the resulting dial was protected as a dibenzyl ether. The t-butyklimethylsilyl
ether was cleaved and the resulting alcohol was oxidized to labile
aldehyde 9. Addition of the allylic anion generated from (B)-2-methyl-2-(4-methyl-5-phenylthio-3-pentenyl)-l,3dioxolane with lithium naphthalenide to aldehyde under a variety of conditions9 gave exclusively one product with an isomerized cis-Cil,tZ double bond. In order to obtain a tram coniiguration of the double bond, some kind of tunpolung synthon
of the aldehyde carbonyl had to be considered. To this end, the aldehyde was
transformed to the cyanohydrin trimethylsilyl ether which was depmtonated and alkylated with the corresponding tram allylic bromide to give cyanohydrin derivative 10. lo Exposure of 10 to TBAP in THP for 10 min (prolonged reaction time causes epimerization of the a-carbon) gave ketone 11. This labile ketone was immediately reduced with LAH to give a 1:l mixture of isomeric alcohols; each isomer was carried through the following synthesis starting with conversion to pivalates. Keto aldehyde 12 was macrocyclized with TiC1s/Zn-Cull
in mfluxing
DME to give a mixture (t:c = 4:3,65%) of two isomers 13a and 13b which were separable by chromatography on silica gel (3% ethyl acetate/ petroleum ether). This reaction demonstrated that McMurry coupling methodology could be applied to highly oxygenated substrates, widening the scope of this method. Assignment of the C;, double bond stereochemistry in 13 was made possible by the fact that 13C NMR chemical shifts of methyl groups at trisubstituted olefins differ by about 10 ppm (trans. 13-19 ppm; cis, 22-29 ppm).‘*
Scheme 2
a b. c
OB” 01% 14
16
0 f. 0
---k
0
\
40%
\ T@ 16
OAC 2
Reagents:(a) LAH, 0 ‘C; (b) t-BuMe$iCl, imidazole, DMF, 70 “C, (c) Li, NH,; (d) Ag CO Celite, benzene; (e)l. LDA, CH2=NMe.& 2, MeI. MeOH; 3, DBU, W, (f)l. (n-Bu),NF, THF$ 2. 3% &c1, (g) Ac,O, DMAP, CH2C!12.
2396
With the 14membered ring closed, the mmaining task was to construct the lactone ring (Scheme 2). Thus, trans isomer Wa was converted to diol14 in three steps. The diol was oxidixed to the desired lactone with silver carbonate on Celite13 (Fetixon reagent) in excellent yield. Introduction
of the a-methylene
group was
accomplished with Eschenmoser’s salt. l4 Desilylation of 16. followed by acetylation, gave the tide compound which was identical in all respects to the sample prepared by methylation of natural crassin acetate. Using the same methodology, cis isomer 13b has been transformed to the isomer of the titled compound and both isomers will be evaluated for their biological activities. Acknowledgement: This research was supported by Grant No. GM 27320, National Institute of General Medical Sciences, U.S. Public Health Service. References 1.
Da&en, W. G.; Thiessen, W. E.; Resnick, P. R. .I. Am. Chem. Sot. 1962,84,2015.
2.
Weinheimer, A. J.; Ciereszko, L. S.; Eufford, D. S. Annul. Rev. N. Y. Acad. Sci. 1%0,90,917.
3.
Hossain, M. B.; vsn der Helm, D. Reel. Trav. Chim. Pay-Bas 1%9,88,1413.
4.
McMurry, J. E.; Dushin, R. G. J. Am. Chem. Sot. 1989,111,8928.
5.
Meinwald, J.; Crandall, J. K. J. Am. Chem. Sot. 1%6.88,1292.
6.
For exo selectivity of alkylation on norbornyl ketones, see: Corey, E. J.; Vatakencherry, P. A. J. Am. Chem. Sot. 1%2,84,2611.
7.
Meinwald, J.; Frauenglass, E. J. Am. Gem. Sot. 1960,82,5235.
8.
Lipshultx, B. H.; Pegram, J. J. Tetrahedron Lett. 1980,21,3343.
9.
(a) Screttas, C. G.; Micha-Screttas, M. J. Org. Gem. 1979,44,713; J.Am. Chem. Sot. 1987,10!9,4710.
10.
(a) Evans, D. A.; Truesdale, L. K. Tetrahedron Lett. 1973, 4929; (b) Hertenstein, U.; Hunig, S.; Oller, M. Synthesis 1976,416.
11.
McMurry, J. E.; Kees, K. L. J. Org. Chem. 1977,42,2655.
12.
(a) Martin, G. E.; Matson, J. A.; Turley, J. C.; Weinheimer, A. J. J. Am. Chem. Sot. 19’79, 101, 1888; (b) Kashman, Y.; Carmely, S.; Groweiss, A. J. Org. Chem. N&46,3592.
13.
Fetizon, M.; Golfier, M.; Louis, J-M. Tetrahedron 1975,31,171.
14.
Roberts, J. L.; Borromeo, P. S.; Poulter, C. D. Tetrahedron Lett. W77,1621.
(Received in USA 16 February 1990)
(b) Cohen, T.; Guo, B.; Doubleday, W.